Hanne Mumm

Ethnic differences in Rotterdam criteria and metabolic risk factors in a multiethnic group of women with PCOS studied in Denmark

Objective  Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS).

Hemoglobin A1c as a tool for the diagnosis of type 2 diabetes in 208 premenopausal women with polycystic ovary syndrome

OBJECTIVE To study hemoglobin A1c (HbA1c) as a tool for diagnosing diabetes and to study HbA1c as a cardiovascular risk marker in patients with polycystic ovary syndrome (PCOS). DESIGN Retrospective observational study. SETTING Academic tertiary-care medical center. PATIENT(S) Two hundred eight premenopausal women with PCOS. INTERVENTION(S) Patients underwent clinical evaluation (Ferriman-Gallwey score, body mass index, waist, blood pressure), hormone analyses (T, sex hormone-binding globulin, fasting lipids, insulin, glucose, HbA1c), transvaginal ultrasound, and 2-hour oral glucose tolerance tests (OGTT) measuring capillary blood glucose (BG) at 0 (BG 0) and 120 (BG 120) minutes, insulin, and C-peptide. MAIN OUTCOME MEASURE(S) Results of OGTT, HbA1c values. RESULT(S) Twenty patients were diagnosed with type 2 diabetes during OGTT. The sensitivity and specificity of HbA1c ≥6.5% for the diagnosis of diabetes were 35% and 99%, respectively, compared with the diagnosis established by OGTT. Hemoglobin A1c showed closer correlation with waist, body mass index, and lipid profile than BG 120, suggesting that HbA1c could be a cardiovascular risk marker. CONCLUSION(S) The clinical utility of HbA1c for diagnosing impaired glucose tolerance and type 2 diabetes in PCOS in daily practice is low. Long-term prospective studies are needed to determine whether HbA1c is superior to glucose levels as a cardiovascular risk marker in patients with PCOS.

Age Associated Differences in Prevalence of Individual Rotterdam Criteria and Metabolic Risk Factors During Reproductive Age in 446 Caucasian Women with Polycystic Ovary Syndrome

Clinical manifestations and metabolic risk factors may differ according to age in patients with polycystic ovary syndrome (PCOS). Therefore, a retrospective trans-sectional study in academic tertiary-care medical center was designed. A cohort of 446 premenopausal, Caucasian women (age range 15-49 years) with PCOS were divided into 4 subgroups according to age: group 1 (15-19 years, n=42), group 2 (20-29 years, n=180), group 3 (30-39 years, n=187), group 4 (40-49 years, n=37) and underwent clinical evaluation (Ferriman-Gallwey score, BMI, waist, blood pressure), hormone analyses (sex hormones, fasting lipids, insulin, glucose), transvaginal ultrasound, oral glucose tolerance tests (OGTT) (n=234), and ACTH tests (n=201). BMI, waist, Ferriman-Gallwey score, blood pressure, and lipid profile were higher in older vs. younger age groups whereas androgen levels were lower. Measures of insulin resistance were unchanged between age groups, but glucose levels were significantly higher in older age groups. Rotterdam criteria: The prevalence of PCO and biochemical hyperandrogenism decreased in the oldest age group whereas clinical hyperandrogenism increased. Young patients are characterized by PCO and biochemical hyperandrogenism, whereas older patients are more obese with more severe hirsutism and more cardiovascular and metabolic risk factors.

Smoking is associated with increased adrenal responsiveness, decreased prolactin levels and a more adverse lipid profile in 650 white patients with polycystic ovary syndrome

We investigated the associations between smoking status and metabolic risk factors and sex hormones in polycystic ovary syndrome (PCOS). The study was designed as a retrospective trans-sectional study including 650 white premenopausal women with the diagnoses hirsutism or PCOS divided according to smoking status: non-smokers (NS-PCOS = 390) and smokers (S-PCOS = 260). One hundred and nineteen healthy women were studied as controls (NS-Control = 105, S-Control = 14). Patients and controls underwent clinical evaluation, hormone analyses, transvaginal ultrasound, oral glucose tolerance tests (OGTT) and adrenocorticotropic hormone (ACTH) tests. S-PCOS has significantly higher fasting lipid profile and 17-hydroxyprogesterone levels (basal and ACTH-stimulated) than NS-PCOS patients, whereas prolactin levels were decreased. No significant differences were found in body composition and measures of insulin resistance between NS-PCOS and S-PCOS. PCO was more prevalent in NS-PCOS patients. During multiple regression analyses, smoking was positively associated with 17-hydroxyprogesterone (17OHP) and cholesterol, triglycerides and low-density lipoprotein and inversely associated with prolactin and high-density lipoprotein. We concluded that smoking was associated with increased adrenal responsiveness, decreased prolactin levels and a more adverse lipid profile in PCOS patients, whereas smoking was unassociated with body composition and insulin resistance. Smoking may be associated with the prevalence of individual Rotterdam criteria.

Increased thrombin generation in women with polycystic ovary syndrome A pilot study on the effect of metformin and oral contraceptives

OBJECTIVE Polycystic ovary syndrome (PCOS) is associated with risk factors for cardiovascular disease (CVD) which may be modified by the use of metformin and oral contraceptives (OC). Thrombin generation (TG) measures are risk markers of CVD and address the composite of multiple factors that influence blood coagulation. This prospective, randomized, intervention study evaluated the potential influence of PCOS on TG measures and the effect of OC and/or metformin on TG measures in women with PCOS. MATERIAL AND METHODS Ninety patients with PCOS and 35 controls were included. Patients were randomized to 12 months of treatment with metformin, metformin+OC or OC alone. C-reactive protein (CRP), fibrinogen, total cholesterol, trunk fat mass, body mass index, estradiol, testosterone, sex hormone binding globulin (SHBG) as well as TG measures, i.e. the lag time for formation of thrombin, the endogenous thrombin potential (ETP), peak thrombin concentration (peak) and time to peak were determined at baseline and after 12 months of treatment. RESULTS CRP and total testosterone were significantly higher and SHBG significantly lower in PCOS women than in controls (P=0.012, P<0.001 and P=0.008, respectively). The TG measures ETP, peak and lag time were increased in women with PCOS compared to controls (P<0.01). Significant correlations were observed between TG measures and fibrinogen, CRP, SHBG and fat trunk mass (P>0.01). ETP (P=0.006), peak (P=0.003) and lag time (P=0.023) remained increased after adjustment for these potential confounders. Treatment with OC and metformin+OC further increased ETP (P<0.001) and peak (P<0.005) and reduced time to peak (P<0.04). The increase in ETP was significantly lower in the metformin+OC group than in the OC group (P<0.05). Metformin alone did not affect TG significantly. CONCLUSIONS PCOS is associated with increase in TG measures independent of other risk factors of CVD. OC increase TG measures further and may thus add to the increased risk of CVD already present in women with PCOS.

Hyperandrogenism and phenotypes of polycystic ovary syndrome are not associated with differences in obstetric outcomes

To investigate obstetric outcomes in Danish women with different phenotypes of polycystic ovary syndrome (PCOS) and isolated hyperandrogenism (HA) and describe the risk of adverse obstetric outcomes in women with PCOS and HA compared to controls.

Prolactin is associated with metabolic risk and cortisol in 1007 women with polycystic ovary syndrome

STUDY QUESTION Is there an association between prolactin and markers of metabolic risk in polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Low serum prolactin was a metabolic risk marker in PCOS. WHAT IS KNOWN ALREADY Prolactin is routinely measured to exclude endocrine diseases in PCOS. Recent studies have suggested that prolactin can be used as a marker for metabolic and cardiovascular risk. STUDY DESIGN, SIZE, DURATION Retrospective cross-sectional study in an academic tertiary-care medical center. Data were collected during 1997-2012. Premenopausal women (n = 1007) with hirsutism and/or PCOS and 116 healthy, age-matched controls were included. Prolactin levels were measured in blood samples taken in the morning after a minimum of 2 h awakening time. Macroprolactinemia was excluded by the precipitation of serum with polyethylene glycol in patients with increased prolactin levels. PARTICIPANTS/MATERIALS, SETTING, METHODS Serum prolactin levels were measured along with a clinical evaluation (Ferriman-Gallwey score, BMI, waist circumference, blood pressure) plus hormone analyses (sex hormones, fasting lipids, insulin, glucose), transvaginal ultrasound, and oral glucose tolerance (n = 234) and adrenocorticotrophic hormone tests (n = 201). All patients had prolactin levels below the upper reference limit (23 µg/l). MAIN RESULTS AND THE ROLE OF CHANCE Prolactin levels were significantly lower in patients versus controls; median (quartiles) prolactin levels 7 (5-10) versus 9 (7-13) µg/l (P < 0.001). In the patient population prolactin levels were inversely associated with age, smoking status, waist circumference, total cholesterol, triglyceride and low-density lipoprotein (LDL) and positively associated with high-density lipoprotein, estradiol, total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone and cortisol levels. In multiple regression analyses, prolactin was inversely associated with LDL and positively associated with estradiol, 17-hydroxyprogesterone and cortisol after correcting for age, BMI and smoking status in patients with PCOS. LIMITATIONS, REASONS FOR CAUTION The study design was cross-sectional and prospective studies are needed to further determine the impact of prolactin levels on cardiovascular outcomes. Patients included in the study were relatively lean and only 20 had diabetes, which could have affected our findings. In addition, the collection of blood samples when estrogen levels were low (follicular phase) could be related to the lower levels of prolactin. Furthermore, as prolactin is secreted in a pulsatile manner, several measures of prolactin may be needed to further investigate associations between prolactin and metabolic risk. WIDER IMPLICATIONS OF THE FINDINGS Our findings of inverse associations between prolactin levels and metabolic risk markers are supported by studies in populations of women without PCOS. The association between prolactin and adrenal activity should be evaluated in future studies. STUDY FUNDING/COMPETING INTERESTS This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. There are no conflicts of interest to declare.

Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycemia in PCOS

Context Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. Setting Outpatient clinic. Patients and interventions Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. Main outcome measures Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. Results Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. Conclusions AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.

Prevalence and possible mechanisms of reactive hypoglycemia in polycystic ovary syndrome

STUDY QUESTION What is the prevalence of reactive hypoglycemia (RH) in polycystic ovary syndrome (PCOS) versus age- and body mass index (BMI)-matched healthy controls. SUMMARY ANSWER The prevalence of RH was increased in PCOS versus controls. WHAT IS KNOWN ALREADY Previous studies suggested an increased prevalence of RH in PCOS. STUDY DESIGN, SIZE, DURATION Cross-sectional study of 88 women with PCOS and 34 healthy age- and BMI-matched controls. PARTICIPANTS/MATERIALS, SETTING, METHODS Eighty-eight women with PCOS and 34 age- and BMI-matched controls were included. The study was conducted at Odense University Hospital, Denmark. Participants underwent 5 h oral glucose tolerance test (5 h OGTT). Indices of insulin resistance, β-cell function, and area under the curve (AUC) for glucose, insulin and C-peptide were calculated. Insulin clearance was estimated as 5 h AUC C-peptide/insulin. RH was defined as blood glucose ≤3.3 mmol/l during 5 h OGTT. MAIN RESULTS AND THE ROLE OF CHANCE RH occurred in 15/88 (17%) women with PCOS versus 0/34 controls ( ITALIC! P = 0.01). Nine out of 15 women with RH were obese and 6 were lean ( ITALIC! P = 0.42). Obese patients with RH had significantly higher 5 h AUCs insulin and C-peptide compared with lean patients with RH ( ITALIC! P = 0.02 and 0.04, respectively). Obese patients with RH had significantly lower 5 h AUC C-peptide/insulin versus obese patients without RH ( ITALIC! P = 0.02). In lean patients with RH, 5 h AUCs insulin and C-peptide were similar to lean controls. LIMITATIONS, REASONS FOR CAUTION The 5 h OGTT was used to diagnose RH and may be a limitation of the study. Although the 5 h OGTT is the most widely accepted method, no gold standard exists in terms of diagnosing RH. The 5 h OGTT was suggested to over-estimate the incidence of RH compared with meal test. WIDER IMPLICATIONS OF THE FINDINGS The study supports previous suggestions of increased prevalence of RH in women with PCOS compared with controls. STUDY FUNDING/COMPETING INTERESTS This study was funded by Jacob Madsens and Olga Madsens Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møllers Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER The trial was registered at www.clinicaltrials.gov (registration numbers NCT00451568 (patients) and NCT01995773 (controls)).

The Effect of 12 Month Randomized Treatment with Oral Contraceptivesand/or Metformin on GLP-1 in Polycystic Ovary Syndrome

Context: Insulin resistance could be associated with decreased GLP-1 secretion in PCOS. Treatment with oral contraceptives (OCP) and/or metformin (M) may affect GLP-1 levels and the increased risk of reactive hypoglycaemia (RH) in PCOS. Setting: Outpatient clinic. Patients and interventions: Randomized, controlled clinical trial. 90 patients with PCOS were randomized to 12 month treatment with OCP (150 mg desogestrel+30 microgram ethinylestradiol), M (2 g/day), or M+OCP. 5-hour oral glucose tolerance tests (5 h OGTT) were performed before and after the intervention period. 65 patients completed the study. 34 weight matched healthy women were included as controls. Main outcome measures: Changes in GLP- 1, insulin, C-peptide, and blood glucose during 5 h OGTT. Results: Treatment with M was superior to OCP regarding weight reduction (the median (quartiles) weight change during M treatment was -3.0 (-10.3; 0.6) kg) and decreased insulin and C-peptide levels during 5 h OGTT, whereas no significant changes were found in GLP-1 levels during 5 h OGTT. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after medical treatment (P<0.01). Reactive hypoglycemia after medical intervention was more common after treatment with M+P, increased from 3/23 to 6/23 (p=0.01) and was associated with higher insulin and Cpeptide levels during 5 h OGTT, but was unassociated with BMI and GLP-1. GLP-1 levels were comparable in patients with PCOS vs. controls. GLP-1 levels were significantly lower in obese vs. lean patients (AUC GLP-1 during 5 h OGTT: 36.3 (30.8; 42.4) vs. 41.6 (37.2; 48.9) 102 mmol/l*h, p<0.001). 5 h AUC GLP-1 levels were inversely associated with BMI in patients with PCOS (r=-0.34, p<0.004). Conclusions: M treatment was associated with weight loss and increased insulin sensitivity compared to OCP, whereas GLP-1 levels were unchanged. Increased insulin levels during M+P treatment could be associated with increased risk of hypoglycemia.